Project Summary: Alzheimer's Disease (AD) and AD-related dementias (ADRDs; e.g. Frontotemporal Dementia, Lewy Body Dementia, etc.) are crippling neurodegenerative disorders. Notably, the onset of these diseases is strongly correlated with aging. In spite of decades of research and clinical effort, cures for AD and ADRDs remain elusive. Indeed, Alzheimer's has become the 6th most frequent cause of death in the USA. New hypotheses and mechanisms for Alzheimer's and ADRDs are urgently needed to guide novel therapeutic approaches: an emerging candidate contributor to Alzheimer's and ADRD is the LINE-1 retrotransposon, which becomes deregulated during aging and thus correlates with Alzheimer's / ADRD onset. One hypothetical mechanism by which LINE-1 may contribute to Alzheimer's / ADRD is through its exacerbation of cellular senescence. Senescence is a phenomenon by which normal cells stop dividing; these cells accumulate with advancing age and are found at the locations of dysfunction in age-related diseases. In mice, senescent cells have been shown to shorten life and actively drive age-related neurodegeneration; preventing senescent cell accumulation decreases tau-dependent degeneration and cognitive decline. AD patients exhibit increased indicators of cellular senescence. It is increasingly clear that senescent cells are not inert, but instead drive tissue deterioration via the senescence-associated secretory phenotype - secreting a variety of growth factors and pro- inflammatory cytokines. LINE-1 retrotransposons have recently been shown to drive progression of the senescence-associated secretory phenotype, and thus, LINE-1 is an important agent of cellular senescence. LINE-1 activation is also associated with AD related Tau pathologies. The LINE-1 encoded ORF2p enzyme (endonuclease and reverse transcriptase) is often flagged as a source of pathological cellular insults, e.g. via new, mutagenic LINE-1 insertions and contributions to chromosomal instability. However, the effects of LINE-1 expression extend beyond DNA damage. Numerous mechanisms may be at play, including the titration of normally homeostatic host factors away from their physiologic functions and into LINE-1 ribonucleoprotein granules, as well as the production of immunity-and-inflammation-triggering cytoplasmic LINE-1 DNA:RNA hybrids; indeed, the latter is now understood to be a key component of LINE-1?s role in cellular senescence. Moreover, LINE-1 also mobilizes Alu and other non-autonomous retrotransposons. Taken all together, LINE-1 is imbued with a prodigious array of opportunities for pathologic interventions in cell function. We will capture and analyze LINE-1 ribonucleoproteins in senescent cells and Alzheimer's / ADRD afflicted brain tissues, gathering additional evidence to support or refute the hypothesis that LINE-1 is a causal agent in Alzheimer's / ADRD.